8-Methoxypsoralen(9-methoxy-7H-furo[3,2g][1]benzopyran-7-one) is a compound of the formula ##STR1##
Methoxsalen, as it is more commonly known, has been obtained from natural sources, namely from the fruit of the Ammi Majus Linn plant. See, for example, Fahmy et al., "Ammi Majus Linn. Pharmacognostical Study and Isolation of Crystalline Constituent, Ammoidin", Quart. J. Pharm. and Pharmacol., 20: 281, (1948). In addition, a synthetic process for the preparation of methoxsalen is described in U.S. Pat. No. 4,130,568.
It is known that either the topical application or oral ingestion of psoralens and certain isomers of furocoumarins, have an effect on the responsiveness of human skin to sunlight. These psoralen compounds, including methoxsalen, have long been used in the treatment of skin diseases such as vitiligo which is characterized by a spotty loss of pigmentation of the skin and psoriasis. Methoxsalen has been used, in combination with exposure of the patient to ultra-violet light, to enhance the repigmentation of the skin by increasing melanogenesis. In this treatment of psoriasis (known as PUVA therapy), methoxsalen is given orally in doses adjusted to body weight. Thus, the dose can range from 20 mg for a subject of 50 kg. body weight to 50 mg for a subject of over 80 kg. body weight.
Heretofore, methoxsalen for oral administration was used in the form of gelatin capsules containing about 10 mg of the drug in dry powdered form with such excipients as starch or lactose. The particle size of methoxsalen varied depending on the method and degree of particle size reduction.
Since, in general, the dissolution rate of an orally administered drug, which influences the rate at which the drug enters the blood stream, is related to its particle size, attempts to increase the dissolution rate of methoxsalen, administered in capsules, by reduction in its particle size using such standard procedures as ultrasonic deaggregation (micronization) or comminution were tried. However, since methoxsalen crystals are fluffy, needle-like and reactant to flow, these procedures had several unacceptable features. Thus, in comminution, clogging of the screens is common while in micronization using jet air milling there is considerable loss of drug. Further, the airborne dust resulting from these milling procedures can be hazardous to operating personnel due to the irritant nature of methoxsalen on both the skin and mucous membranes.
Even using the above techniques with their drawbacks, a level of methoxsalen in the blood could only be achieved some two hours after oral administration. The subsequent ultraviolet radiation treatment of a patient had to be deferred until this peak blood-level was achieved, causing much inconvenience to the patient.
The need for an oral dosage form containing methoxsalen in a fine particle size range (e.g. 1-300 microns) is, therefore, apparent.
It was known that the dissolution rate of the antibiotic griseofulvin could be significantly increased by incorporation into melts with a polyethylene glycol (PEG 6000). However, griseofulvin in the solidified melt was in the amorphous form (Chiou and Riegelman, J. Pharm. Sci., 58, No. 12, 1505-1510; 59, No. 7, 937-942; 60, No. 9, 1377-1380). U.S. Pat. No. 3,972,999 discloses a melt of amorphous griseofulvin and certain polyglycolides.